title: Estrogen mediates neuroprotection and anti-inflammatory effects during EAE through ERα signaling on astrocytes but not through ERβ signaling on astrocytes or neurons.
abstract: Estrogens can signal through either estrogen receptor α (ERα) or β (ERβ) to ameliorate experimental autoimmune encephalomyelitis (EAE), the most widely used mouse model of multiple sclerosis (MS). Cellular targets of estrogen-mediated neuroprotection are still being elucidated. Previously, we demonstrated that ERα on astrocytes, but not neurons, was critical for ERα ligand-mediated neuroprotection in EAE, including decreased T-cell and macrophage inflammation and decreased axonal loss. Here, we determined whether ERβ on astrocytes or neurons could mediate neuroprotection in EAE, by selectively removing ERβ from either of these cell types using Cre-loxP gene deletion. Our results demonstrated that, even though ERβ ligand treatment was neuroprotective in EAE, this neuroprotection was not mediated through ERβ on either astrocytes or neurons and did not involve a reduction in levels of CNS inflammation. Given the differential neuroprotective and anti-inflammatory effects mediated via ERα versus ERβ on astrocytes, we looked for molecules within astrocytes that were affected by signaling through ERα, but not ERβ. We found that ERα ligand treatment, but not ERβ ligand treatment, decreased expression of the chemokines CCL2 and CCL7 by astrocytes in EAE. Together, our data show that neuroprotection in EAE mediated via ERβ signaling does not require ERβ on either astrocytes or neurons, whereas neuroprotection in EAE mediated via ERα signaling requires ERα on astrocytes and reduces astrocyte expression of proinflammatory chemokines. These findings reveal important cellular differences in the neuroprotective mechanisms of estrogen signaling through ERα and ERβ in EAE.
authors.affiliation: Departments of Neurology and Neurobiology, University of California Los Angeles, Multiple Sclerosis Program, Los Angeles, California 90095, USA.
authors.forename: Rory D
authors.initials: RD
authors.lastname: Spence
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Wisdom
authors.forename: Yuan
authors.initials: Y
authors.lastname: Cao
authors.forename: Haley M
authors.initials: HM
authors.lastname: Hill
authors.forename: Chandler R L
authors.initials: CR
authors.lastname: Mongerson
authors.forename: Briana
authors.initials: B
authors.lastname: Stapornkul
authors.forename: Noriko
authors.initials: N
authors.lastname: Itoh
authors.forename: Michael V
authors.initials: MV
authors.lastname: Sofroniew
authors.forename: Rhonda R
authors.initials: RR
authors.lastname: Voskuhl
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal; D051401:Aquaporin 4 / Q000502:physiology; D001253:Astrocytes / Q000187:drug effects*; D001369:Axons / Q000502:physiology; D002452:Cell Count; D018932:Chemokine CCL2 / Q000235:genetics / Q000502:physiology; D054410:Chemokine CCL7 / Q000235:genetics / Q000502:physiology; D003711:Demyelinating Diseases / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000473:pathology* / Q000517:prevention & control*; D047628:Estrogen Receptor alpha / Q000187:drug effects*; D047629:Estrogen Receptor beta / Q000187:drug effects*; D004967:Estrogens / Q000494:pharmacology*; D005911:Gliosis / Q000473:pathology; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents; D015398:Signal Transduction / Q000187:drug effects*; D013116:Spinal Cord / Q000473:pathology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D051401:Aquaporin 4; D018932:Chemokine CCL2; D054410:Chemokine CCL7; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D018696:Neuroprotective Agents